In 1054 he quarrelled with legates sent by Pope Leo IX over church practises which had been differing from the Roman Church for centuries, especially the use of unleavened bread in the Eucharist. The legates excommunicated him, and he likewise excommunicated them, starting the Great Schism. This schism led to the end of the alliance between the Emperor and the Papacy and caused later Popes to ally with the Normans against the Empire. In 1965, those excommunications were rescinded by Pope Paul VI and Patriarch Athenagoras when they met in the Second Vatican Council. This was a significant step towards restoring communion between Rome and Constantinople.

Michael also quarrelled with Emperor Isaac I Comnenus over confiscation of church property. Isaac planned to depose Michael when Michael suddenly died in 1059, though there was no suspicion that he was murdered.